The role of extracellular matrix in tumour angiogenesis: the throne has NOx servants

Abstract

The extracellular matrix (ECM) dynamics in tumour tissue are deregulated compared to the ECM in healthy tissue along with disorganized architecture and irregular behaviour of the residing cells. Nitric oxide (NO) as a pleiotropic molecule exerts different effects on the components of the ECM driving or inhibiting augmented angiogenesis and tumour progression and tumour cell proliferation and metastasis. These effects rely on the concentration of NO within the tumour tissue, the nature of the surrounding microenvironment and the sensitivity of resident cells to NO. In this review article, we summarize the recent findings on the correlation between the levels of NO and the ECM components towards the modulation of tumour angiogenesis in different types of cancers. These are discussed principally in the context of how NO modulates the expression of ECM proteins resulting in either the promotion or inhibition of tumour growth via tumour angiogenesis. Furthermore, the regulatory effects of individual ECM components on the expression of the NO synthase enzymes and NO production were reviewed. These findings support the current efforts for developing effective therapeutics for cancers.

Differences of Angiogenesis Factors in Tumor and Diabetes Mellitus

“…NO can be synthesized by three nitric oxide synthases (NOS), and NO is mainly produced by endothelial nitric oxide synthase (eNOS). 33 Under physiological conditions, NOS in vascular endothelial cells can synthesize small doses of NO, while HIF-1, VEGF, and SDF-1 can further increase NO release through various pathways under ischemia and hypoxia conditions. The effect of NO may depend on the environment and cell type and concentration.…”

“…The effect of NO may depend on the environment and cell type and concentration. 33 Low concentrations of NO increases intracellular cyclic guanosine monophosphate (cGMP) in response to VEGF stimulation of angiogenesis, while high concentrations inhibits angiogenesis. 34 What is interesting is that not only VEGF and HIF-1 regulate the synthesis and secretion of NO in various ways, 34,35 but also eNOS and NO in response are believed to increase VEGF expression and HIF-1 activity, thereby stimulating angiogenesis.…”

“…However, NO has multiple effects on tumor biology, depending on the concentration of NO in the tumor tissue, duration of exposure, NOS activity level, tumor type, nature of the surrounding microenvironment, and sensitivity of related cells to NO. 33 So different experiments have yielded different results: Tijana Suboticki et al proved through DNA Sequencing, Isolation ofTotal RNA, RT-PCR, Western Blot and other methods that there is a positive correlation between VEGF and eNOS levels in granulocytes of MPNs. However, Amir M. Alsharabasy et al explored the regulatory effect of NO on MMPs.…”

“…However, Amir M. Alsharabasy et al explored the regulatory effect of NO on MMPs. 33,34,38 In the treatment of diabetes, chronic morphine treatment 39 and Metformin 40 have achieved good results in animal models. However, in the treatment of cancer, few reports have been on the therapeutic effect achieved by inhibiting NO.…”

“…6,45 Moreover, the activity of these MMPs is regulated in various ways, such as NO, tissue inhibitor of metalloproteinases (TIMPs), etc. 33,46 Also, activated protein1 (AP-1) and NF-kB are believed to be related to the expression of MMP-9. However, MMP-9 may harm angiogenesis by producing angiostatin.…”